Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+regulatory T cells

Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.

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Effective expansion of forkhead box P3+ regulatory T cells via early secreted antigenic target 6 and antigen 85 complex B from Mycobacterium tuberculosis

Molecular Medicine Reports ◽

10.3892/mmr.2014.3033 ◽

2014 ◽

Vol 11 (4) ◽

pp. 3134-3142 ◽

Cited By ~ 5

Author(s):

YING-E WU ◽

ZHONG-REN DU ◽

YING-MU CAI ◽

WEN-GUANG PENG ◽

GAO-ZHE ZHENG ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Regulatory T Cells ◽

Forkhead Box P3 ◽

Forkhead Box ◽

Effective Expansion ◽

Antigen 85

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Neuroprotective Effects of Ex Vivo Expanded Regulatory T Cells on Trimethyltin Induced Neurodegeneration in Mice

10.21203/rs.3.rs-742244/v1 ◽

2021 ◽

Author(s):

Seon-Young Park ◽

HyeJin Yang ◽

Minsook Ye ◽

Xiao Liu ◽

Insop Shim ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Adoptive Transfer ◽

Calcium Binding ◽

Microglial Activation ◽

Time Lapse ◽

Inhibitory Effects ◽

Immune Balance ◽

Hippocampal Neurodegeneration

Abstract BackgroundTrimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice.MethodsCD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after mouse sacrifice. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assy (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20.ResultsAdoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time lapse imaging in a Treg/microglia co-culture system.ConclusionsThese data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.

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